Time-course global proteome analyses reveal an inverse correlation between Aβ burden and immunoglobulin M levels in the APPNL-F mouse model of Alzheimer disease.
Hansen WangDeclan WilliamsJennifer GriffinTakashi SaitoTakaomi C SaidoPaul E FraserEkaterina RogaevaGerold Schmitt-UlmsPublished in: PloS one (2017)
Alzheimer disease (AD) stands out amongst highly prevalent diseases because there is no effective treatment nor can the disease be reliably diagnosed at an early stage. A hallmark of AD is the accumulation of aggregation-prone amyloid β peptides (Aβ), the main constituent of amyloid plaques. To identify Aβ-dependent changes to the global proteome we used the recently introduced APPNL-F mouse model of AD, which faithfully recapitulates the Aβ pathology of the disease, and a workflow that interrogated the brain proteome of these mice by quantitative mass spectrometry at three different ages. The elevated Aβ burden in these mice was observed to cause almost no changes to steady-state protein levels of the most abundant >2,500 brain proteins, including 12 proteins encoded by well-confirmed AD risk loci. The notable exception was a striking reduction in immunoglobulin heavy mu chain (IGHM) protein levels in homozygote APPNL-F/NL-F mice, relative to APPNL-F/wt littermates. Follow-up experiments revealed that IGHM levels generally increase with age in this model. Although discovered with brain samples, the relative IGHM depletion in APPNL-F/NL-F mice was validated to manifest systemically in the blood, and did not extend to other blood proteins, including immunoglobulin G. Results presented are consistent with a cause-effect relationship between the excessive accumulation of Aβ and the selective depletion of IGHM levels, which may be of relevance for understanding the etiology of the disease and ongoing efforts to devise blood-based AD diagnostics.
Keyphrases
- mouse model
- early stage
- high fat diet induced
- mass spectrometry
- white matter
- high resolution
- resting state
- gene expression
- genome wide
- squamous cell carcinoma
- mild cognitive impairment
- skeletal muscle
- risk factors
- body mass index
- amino acid
- cerebral ischemia
- multiple sclerosis
- liquid chromatography
- protein protein
- small molecule
- wild type
- functional connectivity
- physical activity
- sentinel lymph node
- brain injury
- binding protein
- insulin resistance
- metabolic syndrome
- capillary electrophoresis